It is generally known that some kinds of fluorocarbon emulsions have utility as resuscitative fluids or blood substitutes, wherein the fluorocarbon acts as an oxygen transport medium in place of the hemoglobin function in natural blood of mammals.
Fluorocarbon particle size has been identified as a factor in toxicity and has adverse effects upon biological systems, such as test animals wherein particles having a size of 0.4 micron or average particle size of greater than 0.2 micron have been identified as problematic to effective maintenance of such test animals.
In light of the requirement for extremely small fluorocarbon particle size in stable emulsions for blood substitute or oxygen transport utility, difficulties in appropriate emulsification and stability under general storage conditions exist due to the incompatibility of the fluorocarbons and their aqueous medium in which they are emulsified. Further, it has generally been found that surfactants pose a problem of biocompatibility.
Various fluorocarbons have been utilized for experimentation in the area of oxygen transport in mammals, including perfluorotripropylamine. perfluorodecalin, perfluoromethyldecalin and perfluorotributylamine.
Various emulsifiers have been utilized to emulsify fluorocarbons in an aqueous phase, including the PLURONIC.RTM. surfactants having a chemical structure of polyoxyethylene-polyoxypropylene copolymer, lipids, most notably lecithin from egg yolk phospholipids and soybean phospholipids and the monoglyceride of fatty acid selected from the group consisting of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, palmitoleic acid, oleic acid, linolenic acid and arachidonic acid.
These fluorocarbons and emulsifiers are dispersed in aqueous media having physiological acceptance, including isotonic solutions such as Tyrode solution, Ringer's solution, lactated Ringer's solution or Ringer's solution containing glucose, and in some instances such aqueous media include emulsifier adjuvants, such as traces of fatty acid.
In U.S. Pat. No. 3,962,439, an artificial blood is set forth having a perfluorocarbon of 9-11 carbon atoms, a particle size of 0.05-0.3 microns and an emulsifier of a phospholipid and an emulsifying adjuvant of a fatty acid, its salt or the monoglyceride of such fatty acid. The fluorocarbon comprises a 10-40% weight to volume concentration in an emulsion containing 2-6% weight/volume of a phospholipid and minor amounts of fatty acid.
In U.S. Pat. No. 4,397,870 a process is set forth for the prolonged stability of perfluoro compounds in animals and humans comprising injecting an emulsifying agent into the perfused individual. The patent recites that the perfluoro compound represents 15-40% volume per volume of the total mixture which corresponds to 30-75 percent weight per volume and 7-9% weight per volume of lecithin.
U.S. Pat. No. 4,423,077 describes a stable emulsion of perfluoro compounds having a content of 30-75% weight per volume and a 7-9% weight per volume of a lipid which coats the perfluoro compound in a physiologically acceptable aqueous medium. The emulsion of this patent has a particle size of approximately 0.1 micron and 95% of the particles had diameters below 0.2 microns.
U.S. Pat. No. 4,497,829 is directed to stable emulsions prepared by dispersing a purified lipid in a physiologically acceptable aqueous medium by sonication, adding perfluoro compound to the dispersion, sonicating the mixture of lipid in perfluoro compound to form an emulsion of lipid-coated particles of perfluoro compound and centrifuging the emulsion formed to separate oversized particles.
The present inventors are aware of work that produced low levels of perfluorochemicals (0-50 wt/vol %) in LIPOSYN.RTM.II nutrient emulsion, available from Abbott Laboratories. North Chicago, Ill. That work was not capable of producing higher perfluorochemical concentrations.
The present invention provides an advance over the prior art of artificial blood media to provide high fluorochemical concentrations, decreased particle size, increased stability without freezing and longer shelf life for an oxygen transport media useful in mammals. The high level concentrations of fluorochemical are particularly important due to the necessity to carry sufficient oxygen to living tissues.